KR20070021224A - Rapid setting calcium phosphate cements - Google Patents

Abstract

In accordance with the present invention, methods are provided for producing compositions such as pastes or clays that are set at high speed into rigid calcium phosphate products. In the methods herein, anhydrous reactants including calcium and phosphate sources as well as monovalent cationic phosphate dihydrogen salts are combined with the setting fluid and the combined reactants are mixed to produce a settable composition. It is a feature of the present invention that the cements are set at high speed into the rigid product compositions. In addition, the compositions themselves as well as kits for preparing them are provided. The methods and compositions produced thereby are used in a variety of applications, including hard tissue reconstruction applications.

Description

RAPID SETTING CALCIUM PHOSPHATE CEMENTS}

The present invention is a partial application of US Patent Application No. 10 / 850,985, filed May 20, 2004, the disclosure of which is incorporated herein by reference.

Calcium phosphate cements prepared by combining anhydrous component (s) and a liquid to form a flowable paste-like material that can be sequentially set into solid calcium phosphate products are highly promising for use as structural materials in orthopedic and dentistry. For example, it is desirable to have a substance set into calcium phosphate mineral product that can inject fluids into the reticulated bone voids and withstand physiological loads. Materials set into solid calcium phosphate mineral products are of particular interest in that they closely resemble the natural bone mineral phase and are sensitive to remodeling, and are extremely interesting to use such products in orthopedic and related fields.

Numerous different calcium phosphate formulations have been developed, but there is still a need to develop more advanced formulations. Of particular interest is the development of formulations that are quickly set into rigid materials. The present invention provides such formulations.

Related literature

Interested US patents are as follows: 6,375,935; 6,139,578; 6,027,742; 6,005,162; 5,997,624; 5,976,234; 5,968,253; 5,962,028; 5,954,867; 5,900,254; 5,697,981; 5,695,729; 5,679,294; 5,580,623; 5,545,254; 5,525,148; 5,281,265; 5,092,888; 5,013,323; 4,990,163; 4,497,075; 4,429,691; 4,161,511 and 4,160,012.

In accordance with the present invention, methods are provided for producing compositions such as pastes or clays that are set at high speed into rigid calcium phosphate products. In the methods herein, anhydrous reactants including calcium and phosphate sources as well as monovalent cationic phosphate dihydrogen salts are combined with the setting fluid and the combined reactants are mixed to produce a settable composition. It is a feature of the present invention that the cements are set at high speed into the rigid product compositions. In addition, the compositions themselves as well as kits for preparing them are provided. The methods and compositions produced thereby are used in a variety of applications, including hard tissue reconstruction applications.

In accordance with the present invention, methods are provided for producing compositions such as pastes or clays that are set at high speed into rigid calcium phosphate products. In the methods herein, anhydrous reactants including calcium and phosphate sources as well as monovalent cationic phosphate dihydrogen salts are combined with the setting fluid and the combined reactants are mixed to produce a settable composition. It is a feature of the present invention that the cements are set at high speed into the rigid product compositions. In addition, the compositions themselves as well as kits for preparing them are provided. The methods and compositions produced thereby are used in a variety of applications, including hard tissue reconstruction applications.

Before further describing the invention, it is to be understood that the invention is not limited to the specific embodiments disclosed and that such embodiments may of course vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting, and the scope of the present invention will be limited only by the appended claims.

Where a range of values is provided, each intervention value corresponding to one tenth of a lower limit unit value is the range and any other stated range or intervention value of that stated range, unless the context clearly dictates otherwise. It is included in the present invention between the upper limit and the lower limit of. The upper and lower limits of these similar ranges may be independently included in the smaller ranges, may be included in the present invention, and apply to any specifically excluded limit of the stated ranges. Where the stated range includes one or all of the limits, the range excluding one or all of such included limits is also included in the present invention.

The methods cited herein may be performed in any order of logically possible re-cited events, as well as in a re-cited order of events.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein may be used to practice or test the present invention, the preferred methods and materials are described below.

All publications mentioned herein are incorporated herein by reference and describe methods and / or materials in connection with those cited by the publications.

As used in this specification and the appended claims, it should be noted that the singular forms “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. do. It should also be noted that the claims may be drafted to exclude any elements. As such, this statement is intended to serve as antecedent principles to the use of exclusive terms such as "alone", "only" and related to the re-quotation of claimed elements or the use of "negative" limitations.

The publications discussed herein are provided solely for their disclosure prior to the filing date of the present invention. Nothing should be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Moreover, the announcement dates provided may differ from the actual announcement dates that need to be independently verified.

In further describing the present invention, the methods herein are described first, followed by compositions produced accordingly, kits for use in preparing the same and methods for using the compositions in hard tissue, eg bone reconstruction methods. Will be.

Methods

In the methods herein, the anhydrous reactants, including the calcium source and the phosphate source, as well as the sodium dihydrogen phosphate salt are sufficient conditions to produce a flowable composition that is set at high speed into a settable composition, such as a rigid calcium-phosphate containing product. Under pressure, even when immersed in a fluid environment.

In the methods of the invention, the anhydrous reactants include a calcium source and a phosphate source. Anhydrous reactants are typically particle compositions, e.g. powders, wherein the particle size of the components of certain compositions typically ranges from about 1 to about 1000 microns, typically from about 1 to about 500 microns, more commonly from about 1 to about 200 microns. .

As mentioned above, the anhydrous reactants include a calcium source and a phosphate source. The calcium source and the phosphate source may be present as a single compound or in two or more compounds. As such, the single calcium phosphate present in the anhydrous reactants can be a calcium source and a phosphate source. Alternatively, two or more compounds may be present in the anhydrous reactants, where the compounds may be calcium, phosphate or compounds including calcium and phosphate. Interesting calcium phosphate sources that may be present in the anhydrous reactants are: DCPD (dicalcium phosphate dihydrate, blushite or CaHPO ₄ 2H ₂ O), ACP (amorphous calcium phosphate or Ca ₃ (PO _{4) ) 2 H 2 O), DCP} ( dicalcium phosphate, Monet tight or CaHPO _4), α- and _{β- (Ca 3 (PO 4)} 2) the tricalcium phosphate, calcium phosphate used, including both (Ca ₄ (PO ₄ ) ₂ O, etc. Interesting calcium sources include, but are not limited to, calcium carbonate (CaCO ₃ ), calcium oxide (CaO), calcium hydroxide (Ca (OH) ₂ ), and the like. Trailing phosphate sources include, but are not limited to, phosphoric acid (H ₃ PO ₄ ), all soluble phosphates, and the like.

In certain embodiments, the anhydrous reactive portion or component of the cement has an average particle size of less than about 8 μm as disclosed in co-pending US patent application Ser. No. 10 / 900,029 (Horiba LA-300 Laser Diffraction Particle Size Analyzer (version for Windows 95) 3.30 software) (as measured using Irvine, Calif.) And calcium and / or phosphate anhydrous reactants, the disclosures of which are incorporated herein by reference. As such, the anhydrous reactant component of the cement, which may include one or more unique anhydrous reactants, includes reactants having an average particle size of less than about 8 μm and a narrower particle size distribution. The average particle size of such reactants may vary in a range from about 1 to about 6 μm, including from about 1 to about 7 μm, for example from about 1 to about 5 μm, in certain embodiments, and in certain embodiments the average particle size. May be about 1, about 2, about 3, and about 4 μm, and in certain embodiments the average particle size is about 3 μm.

This particular reactant of the cement compositions of the present invention is further characterized as having a narrow particle size distribution. Narrow particle size distributions do not exceed the standard deviation of the particles that make up a particular reactant population (as measured using the Horiba LA-300 laser diffraction particle size analyzer (version 3.30 software for Windows 95) (Irvine, CA)). And in certain embodiments does not exceed about 3.0 and does not exceed about 2.5, including, for example, not greater than about 2.0 μm.

Certain reactants of the cement compositions of the present invention have a mode of (Horiba LA-300 laser diffraction particle size analyzer (version 3.30 software for Windows 95) (as measured by Irvine, Calif.)) Mode not exceeding about 8.0, and certain representative In embodiments it is further characterized by not exceeding about 6.0 and not exceeding about 5, including not exceeding about 3.0 μm.

In certain embodiments, the first reactant constitutes the total anhydrous reactants of the composition, thereby making up 100% of the anhydrous component of the composition.

In certain embodiments, the anhydrous reactants are further characterized as comprising a second reactant having an average particle size at least twice greater than the average particle size of the first reactant component, wherein the average particle size of the second reactant is (Horiba LA-300 At least about 9 μm, at least about 10 μm, at least about 20 μm, at least about 25 μm, at least about 30 μm or as measured using a laser diffraction particle size analyzer (version 3.30 software for Windows 95) (Irvine, CA) It may be more than that.

In certain embodiments, the amount of the first reactant component of the anhydrous reactant composition is greater than the total amount of other reactant components that may be present with the second reactant component as described above. In these embodiments, the mass ratio of the first reactant component to the total mass of anhydrous reactants includes about 1 to about 10, for example about 9.5 to about 8.5, such as about 9 to about 7, such as about 9 to 6 days. Can be.

In certain exemplary embodiments, the first reactant component is a calcium phosphate compound having a calcium to phosphate ratio ranging from about 1.0 to about 2.0, including from about 1.33 to about 1.67, such as 1.5. In certain embodiments, the calcium phosphate compound is tricalcium phosphate, such as α- and β-tricalcium phosphate, and in certain representative embodiments, the tripotassium phosphate is α-tricalcium phosphate.

As noted above, a feature of the present invention is that the anhydrous reactants further comprise monovalent cation phosphate dihydrogen salts. Monovalent cation phosphate dihydrogen salts mean salts of phosphate dihydrogen anions and monovalent cations such as K +, Na + and the like, where these salts are one of the hydrating actions, which can be, for example, anhydrides, monohydrates, dihydrates, and the like It may or may not contain the above water molecules. The monovalent cation phosphate dihydrogen salt present in the cement of the present invention may be described by the following formula:

Y ⁺ H ₂ PO ₄ ㆍ (H ₂ O) _n

here,

Y ⁺ is a monovalent cation such as K + or Na +;

n is an integer of 0-2.

In certain exemplary embodiments, the salt may be sodium diphosphate (ie, monobasic sodium phosphate, NaH ₂ PO ₄ ) or its monohydrate (NaH ₂ PO ₄ H ₂ O) or dihydrate (NaH ₂ PO ₄ 2H _2). It is a sodium dihydrogen phosphate salt, such as O).

The amount of monovalent cation phosphate dihydrogen salt present in the anhydrous reactants may vary, but is present in an amount sufficient to provide a rigid acquisition composition that is set at high speed as described in more detail below. In exemplary embodiments, the salt is present in an amount ranging from about 0.10 to about 10 weight percent, including about 0.5 to about 5.0 weight percent, including about 0.5 to about 2.0 weight percent of the total weight of the dry reactants.

Various calcium phosphate cement compositions are known to those skilled in the art, and such cements can be readily modified into the cement of the present invention by including water soluble contrast agents, as described below. Cement compositions that are known to those skilled in the art and that are of interest include the following U.S. patents: 6,027,742; 6,005,162; 5,997,624; 5,976,234; 5,968,253; 5,962,028; 5,954,867; 5,900,254; 5,697,981; 5,695,729; 5,679,294; 5,580,623; 5,545,254; 5,525,148; 5,281,265; 4,990,163; 4,497,075; And 4,429,691, but not limited to these; Its disclosure is incorporated herein by reference.

The proportions or relative amounts of each of the different calcium and / or phosphate compounds in the anhydrous reactant mixture are to be combined with the setting fluid and subsequent setting fluid to provide the desired calcium phosphate product. In many embodiments, the overall ratio of calcium to phosphate in the anhydrous reactants (ie, the ratio of both heterogeneous calcium and / or phosphate compounds in the anhydrous reactants) is about 4: 1 to 0.5: 1, generally About 2: 1 to 1: 1, more commonly about 1.9: 1 to 1.33: 1.

The second component of the cement compositions herein is a setting fluid as summarized above. This setting fluid can be any of a variety of setting fluids known to those skilled in the art. The setting fluids may contain water (its purified in a concentration ranging from about 0.01 to about 2M, such as from about 0.05 to about 0.5M, at a pH ranging from about 6 to about 11, including from about 7 to about 7.5, etc. Forms), an aqueous alkanol solution, such as glycerol, wherein the alkanol is present in small amounts, preferably in an amount of less than about 20% by volume; pH buffered or unbuffered solutions; And various physiologically suitable fluids, including but not limited to solutions of alkali metal hydroxide, phosphate or carbonate, in particular sodium, more particularly sodium phosphate or sodium carbonate.

 Of particular interest to certain embodiments are silicate setting fluids, ie setting fluids that are soluble silicate solutions. Soluble silicate solution means an aqueous solution in which the silicate compound is dissolved and / or suspended. This silicate compound may be any compound that is physiologically compatible and can be dissolved in water. Soluble in water means a concentration of at least about 1%, typically at least about 2%, more commonly at least about 5%, wherein the concentration of silicate used is typically from about 0-0.1 to 20%, generally About 0.01-5 to 15%, more commonly about 5 to 10%.

Representative silicates of interest include sodium silicate, potassium silicate, boron silicate, magnesium silicate, aluminum silicate, zirconium silicate, potassium aluminum silicate, magnesium aluminum silicate, sodium aluminum silicate, sodium methylsilicate, potassium methylsilicate, sodium butylsilicate, sodium Propyl silicate, lithium propyl silicate, triethanol ammonium silicate, tetramethanolamine silicate, zinc hexafluorosilicate, ammonium hexafluorosilicate, cobalt hexafluorosilicate, iron hexafluorosilicate, potassium hexafluorosilicate, nickel hexafluoro Silicates, barium hexafluorosilicates, hydroxyammonium hexafluorosilicates, sodium hexafluorosilicates and calcium fluorosilicates, but are not limited to these. The preparation of sodium hexafluorosilicates is disclosed in US Pat. Nos. 4,161,511 and 4,160,012; Its disclosure is incorporated herein by reference. Of particular interest to many embodiments is sodium silicate solution, anhydrous sodium silicate (Na ₂ SiO ₃ , Na ₆ Si ₂ O ₇ And Na ₂ Si ₃ O ₇ ) are described in Faith's Keyes &Clark's INDUSTRIAL CHEMICALS (1975), pages 755-761.

In certain embodiments, this solution further comprises an amount of phosphate ions, as disclosed in US Pat. No. 10 / 462,075; Its disclosure is incorporated herein by reference.

In certain embodiments, emulsifiers are included in the formulation. Emulsifiers of interest include: polyoxyethylene or polyoxypropylene polymers or copolymers thereof such as polyethylene glycol and polypropylene glycol; Nonionic cellulose ethers such as methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, carboxyethylcellulose and hydroxypropylcellulose, further celluloses such as carboxymethylcellulose sodium, Carboxymethylcellulose calcium, carboxymethyl starch; Polysaccharides produced by microbial fermentation, for example yeast glucans, xanthan gum, b-1,3-glucans (can be straight or branched; eg curdlan, paramilium, pakiman, sclero) Glucan, laminaran); Other natural polymers such as gum arabic, guar gum, carrageenan, tragacanth gum, pectin, starch, gelatin, casein, dextrin, cellulose; Polyacrylamide; Polyvinyl alcohol; Starch; Phosphate starch; Sodium alginate and propylene glycol alginate; gelatin; Amino-containing acrylic acid copolymers and quaternary products derived therefrom, and the like, but are not limited thereto.

In particular embodiments of particular interest, the emulsifier is a cellulose ether, in particular a nonionic cellulose ether, for example carboxymethylcellulose. Carboxymethylcellulose is available from a variety of commercial sources, including, but not limited to, sigma, Hercules, Fluca, and Novient. In certain embodiments, the average molecular weight of the cellulose ether is at least about 1000 Daltons, such as at least about 5000 Daltons, where the average molecular weight may be as high as 10,000 Daltons or more, for example 50,000 Daltons, 100,000 Daltons or more, and In embodiments it may range from about 5,000 to about 100,000 Daltons, for example from about 10,000 to about 50,000 Daltons.

In certain embodiments the proportion of emulsifier in the cement is from about 0.01 to about 10% (w / w). For example, from about 0.05 to about 2.0% (w / w).

When used, emulsifiers may be included in one or both of the liquid and anhydrous reactant components.

In certain embodiments, the cement compositions of the present invention can be inoculated with any of a variety of cells as disclosed in published US patent application 20020098245, the disclosure of which is incorporated herein by reference.

In addition, in certain embodiments, these compositions typically comprise a desalted bone matrix, which may be obtained in frozen or gel form, and is combined in part with the cement composition prior to implantation. Various demineralized bone matrices are known to those skilled in the art, and any convenient / appropriate matrix composition can be used.

One or both of the liquid and dry reactant components may, if desired, adjust the properties of one or more additional reagents (e.g., barium containing reagents) or products, such as photographing agents or contrast agents, so that the compositions It may include an active agent to be prepared by. Such additional components or reagents impart many properties such as organic polymers such as enhanced resorption, angiogenesis, cell introduction and proliferation, mineralization, bone formation, osteoclasts and / or osteoblast growth, etc. Proteins including bone-related proteins (specific proteins of interest include osteonectin, bone salivary protein (Bsp), α-2HS-glycoprotein, bone Gla-protein (Bgp), matrix Gla-protein, bone phosphorus glycoprotein , Bone phosphoproteins, bone proteoglycans, protopridoids, bone morphogenic proteins, cartilage inducers, platelet induced growth factors, skeletal growth factors, and the like); Certain extenders; Inorganic water soluble salts such as NaCl, calcium sulfate; Sugars such as sucrose, fructose and glucose; Pharmaceutical actives such as antibiotics; And the like, but are not limited thereto.

In carrying out the methods herein, an appropriate amount of anhydrous reactants (including monovalent cation phosphate dihydrogen salt) and the setting fluid are combined to produce a settable composition. In other words, the ratio of anhydrous reactants to the setting fluid (ie, liquid to solid ratio) is selected to provide a "settable" composition, wherein the "settable" composition is the first non-solid (also non- The composition proceeding from the gas) state to the second solid state. In many embodiments, the liquid to solid ratio is selected to provide a flowable composition that proceeds from the first non-solid state to the second solid state, and in many embodiments the flowable composition is derived from the viscosity of the modeling clay. It has a viscosity in the range up to it. As such, the liquid to solid ratio used in the methods herein typically ranges from about 0.2 to 1.0, generally about 0.2 to 0.6, and in many embodiments of particular interest are methods of producing paste compositions, where such The liquid to solids ratio used in the methods ranges from about 0.25 to 0.5, typically about 0.3 to 0.45.

As noted above, the required amount of anhydrous reactants, the setting fluid and the contrast agent (which may be separated from or present in one or both of the anhydrous reactants and the setting fluid) may be combined under conditions sufficient to produce the product composition. do. As such, the anhydrous liquid components are typically combined under shaking or mixing conditions such that a homogeneous composition is produced from the anhydrous liquid components. Mixing can be carried out using any convenient means including manual mixing means as disclosed in US Pat. No. 6,005,162 and automatic mixing means as disclosed in WO 98/28068, the disclosures of which are incorporated herein by reference. Quote on. Also of interest is the device disclosed in US Pat. No. 5,980,482, the disclosure of which is incorporated herein by reference.

In certain embodiments, a simple cylindrical tube can be used both as a storage and packaging device and as a mixing and delivery device. The plastic tube or similar container structure is separated into at least two sections, partitions or parts. One section or portion contains the powder component as described above. At least one or more partitions contain the setting fluid, and in certain embodiments, two or more partitions are provided for the setting fluid components, for example it is desirable to keep the heterogeneous components of the setting fluid separately before use ( Or have flexibility in determining the amount of phosphate and silicate ions in the setting fluid used. For example, it may have a two-barrier device made of powder in one partition and the setting fluid of the other. In other embodiments, it may have three partition devices of powder in the first partition, silicate solution of the second partition, and phosphate solution of the third partition. In still other embodiments, a powder in the first partition, a solution of one concentration of one component or all component ions of the second partition wall, and a solution of a second concentration of one component or all component ions of the third partition wall It is possible to have a multi-bulk device in which an embodiment of this type allows a person to "fit" a setting fluid used depending on the particular application in which the cement is to be used. In still other embodiments, it may have a three-barrier device made of a powder of the intermediate component and a setting solution of two other components, each setting solution may be the same or different. Additional partitions may be provided for further components, such as water soluble contrast agents, cement modifiers, etc., if desired.

The two or more partitions are separated from each other by an easily removable barrier that can be easily removed during fabrication of the package cement. Any convenient removable barrier may be present in the device, where an exemplary barrier means of interest is a dialysis back clip or similar means. Other representative barrier means of interest are the frangible barriers as disclosed in WO 98/28068 and 5,362,654; Its disclosures are incorporated herein by reference. When anyone can easily mix, the clip or other barrier means between the regions (liquid (s) and powder) is removed (eg unclipped) and the contents are simply kneaded together manually or by other techniques. do. The steps can be carried out via a second outer covering for sterilization-ie the package elements can be present in the second outer covering for sterilization. The outer covering can then be removed and the contents mixed from the tube can be delivered from one end of the storage / mixing tube using a peristaltic action.

The packaging is intended to assist in combining one or more additional components used during the use / delivery of the product composition, such as removable delivery elements, elements for delivering product cement into an attached delivery element, components It may be further modified to include elements and the like to produce a product composition.

Representative mixed devices and methodologies are described in US Pat. No. 6,375,935; As well as co-pending patent application 10 / 462,075; 10 / 629,321; 10 / 717,171; 10 / 661,356; And 10 / 109,994; The disclosures of which are incorporated herein by reference.

The temperature of the environment in which the combination or mixing of the anhydrous liquid components occurs is sufficient to provide a product with the desired setting and strength properties, and typically ranges from about 0 to 50 ° C, typically about 20 to 30 ° C. Mixing occurs for a period sufficient for the flowable composition to be produced and generally occurs for a period ranging from about 5 to 120 seconds, typically about 10 to 90 seconds, more commonly about 15 to 60 seconds.

In certain embodiments of the present invention, vibration is used in connection with minimal production of orthopedic cement. Used in connection with the manufacture of orthopedic cement means that vibration is used at some point during the period when the cement precursors of the cement, for example liquid and solid reagents or cement components, are combined to produce the flowable cement product composition. Means that. With many orthopedic cements of interest, anhydrous liquid precursors such as powders and setting liquids produce a flowable cement composition product that is set into a solid material over time. In certain embodiments of the present invention, vibration is used, for example, by applying vibrational power, for example ultrasonic or mechanical power, to precursors of the flowable composition during mixing of the precursors. For example, in certain representative embodiments, vibration may be applied to a container or vessel, such as a syringe, where a flowable cement composition is prepared and applied to the flowable cement composition as it is produced.

In these representative particular embodiments, the vibrational power applied to the cement is in the range of about 0.1 Hz to about 100,000 Hz, such as about 5 Hz to about 50,000 Hz, including about 100 Hz to about 5000 Hz, and about 10 microns to about It can have an amplitude in the range of about 1 angstroms to about 5 mm, such as about 1 micron to about 1 mm, including 500 microns.

Vibration power may be applied to the cement components during the manufacturing period or a portion thereof, for example while the initial components are combined, or while the additives are combined with the mixed product of the initial components. In certain representative embodiments, vibration is applied for a period of time ranging from about 1 second to about 5 minutes, such as from about 10 seconds to about 1 minute, including from about 15 seconds to about 30 seconds. Such embodiments are further described in patent applications 10 / 661,356 and 10 / 797,907; Its description is incorporated herein by reference.

The protocols result in a settable composition that can be set at high speed into a rigid calcium phosphate mineral product, as described in more detail below.

Settable Compositions

The settable compositions produced by the methods are compositions that are set at high speed into a biologically suitable, often resorbable and / or remodelable rigid product, wherein the product is not present in the initial reactants, ie And calcium phosphate molecules, which are products of chemical reactions between the initial reactants.

In representative embodiments, the settable compositions are fluid. The term "flowable" is meant to include more liquid compositions as well as pasty compositions. As such, the viscosity time of the flowable compositions of the present invention, defined as the time period after which the mixed composition is injected through standard Luer-lok fittings, is typically about 10 minutes or less, typically about 7 minutes or less, for example about 4 minutes. The range is less than a minute. Of particular interest to many embodiments are paste compositions having injectable viscosities that are injected over a period of about 5 minutes or less, for example about 4 minutes or less. Pastes that remain paste-shaped for an extended period of time can be replaced by bleeding the bone once implanted into the body, which creates blood that borders between the cement and the bone before cement hardens.

The compositions produced by the present invention are set into calcium phosphate mineral containing products. By "containing calcium phosphate minerals" product is meant a solid product comprising at least one, generally predominantly one calcium phosphate mineral. In many embodiments, the calcium phosphate mineral is generally poor crystalline to be resorbable and often remodelable over time when implanted into a physiological site. The calcium to phosphate ratio in the product may vary depending on the specific reactants and the amount used to produce it, but typically is from about 2: 1 to 1.33: 1, typically about 1.8: 1 to 1.5: 1, More commonly in the range of about 1.7: 1 to 1.6: 1. Of particular interest in many embodiments are apatite products, which include hydroxyapatite and calcium-defective analogs thereof, including about carbonate substituted hydroxyapatite (ie, dahlite), and the like. Calcium to phosphate ratios ranging from 1: 1 to 1.33: 1. The compositions of the present invention may, in many embodiments, be set into hydroxyapatite products such as carbonated hydroxyxin apatite, ie, adalite, from about 2 to about 10% of the final product, typically from about 2 to about 8 Carbonate substitution by weight.

The time period required to cure or "set" the compositions can be varied. The setting is measured by a Gilmore needle test (ASTM C266-68) and modified by cement immersed under physiological saline at 37 ° C., where the setting is time after manufacture when the compositions are indented with a needle applied at 135 Newton force. It is defined as The setting time of the cements of the present invention may vary from about 30 seconds to 20 minutes, and in certain embodiments will range from about 30 seconds to 10 minutes. In many embodiments, the flowable composition is set at a clinically relevant time. Clinically relevant time means that the pasty composition is set within less than about 30 minutes, and typically less than about 25 minutes, wherein the composition is at least about 3 minutes, sometimes a combination of precursor liquid and anhydrous cement components. Or remain flowable for at least about 5 minutes after mixing.

A feature of compositions that are set at high speed is that they are set at high speed into the rigid product, as measured by the Gilmore needle test (ASTM C266-68) in terms of setting values. More specifically, these compositions obtain high strength at high speed, so that they can be considered as high speed strength obtaining compositions. As such, at 3 minutes the compositions have a setting of at least about 50 Newtons, for example at least about 75 Newtons, wherein the setting can be as high as 100, 150, 175 or more, for example 250 or more. At 6 minutes, the compositions have a setting of at least about 250 Newtons, for example at least about 275 Newtons, where the setting can be as high as 400 Newtons of 400, 450, 475 or more (eg, 500 or more). At 9 minutes, the compositions have a setting of at least about 425 Newtons, for example at least about 450 Newtons, where the setting can be as high as 600, 700, 725 or more Newtons. At 12 minutes, the compositions have a setting of at least about 600 Newtons, for example at least about 650 Newtons, where the setting can be as high as 700, 750, 775 or more, for example 1200 or more Newtons.

A feature of the compositions of the invention is that they are operable even while they are set into a solid product. As such, they can be manipulated during the setting process without adversely affecting the properties of the final product. For example, during the setting process, screws can be drilled into them without adversely affecting the properties of the final product.

In certain embodiments, the settable compositions may comprise the following phases: (1) a working period during which the composition can be manipulated, eg, delivered to a bone defect site; (2) a setting period during which the composition must be maintained without manipulation; (3) a “drillable” period during which hardware, such as a screw, is inserted or positioned into the composition; And (4) compositions proceeding through a screw tightening period, wherein screws located within the composition during the "drillable" period can be tightened without adversely affecting the composition. In certain embodiments, the working period ranges from about 0.5 minutes to about 5.0 minutes, for example from about 0.5 minutes to about 4.0 minutes after mixing of the components. In certain embodiments, the setting period ranges from about 1 minute to about 15 minutes, for example from about 1 minute to about 10 minutes after mixing of the components. In certain embodiments, the drillable period of time can be undertaken from about 5 minutes to about 10 minutes after mixing of the components and can extend to about 10 minutes to about 15 minutes or more after mixing of the components. In certain embodiments, the screw tightening period range is undertaken from about 10 minutes to about 15 minutes after mixing of the components.

In one exemplary embodiment, the working period is in the range of about 0 to about 2 minutes, for example about 0.5 to about 1 minute after mixing of the components. In this embodiment, the setting period occurs for a period of about 1 minute to about 5 minutes after mixing of the components. In this embodiment, the drillable period of time occurs for a period of about 5 minutes to about 10 minutes after mixing of the components. In this embodiment, the screw-tightening period is undertaken about 10 minutes after mixing of the components.

In another exemplary embodiment, the working period lasts up to about 5 minutes and typically lasts up to about 4 minutes, including 3 minutes after mixing of the ingredients. In this embodiment, the setting period occurs for a period of about 4 minutes to about 10 minutes after mixing of the components. In this embodiment, the drillable period occurs for a period of about 10 minutes to about 15 minutes after mixing of the components. In this embodiment, the screw-tightening period is undertaken about 15 minutes after mixing of the components.

The compressive strength of the product to which the flowable composition is set may vary significantly depending on the particular ingredients used to produce it. Of particular interest to many embodiments is a product having a compressive strength sufficient to at least serve as reticulated bone structural material. Reticulated bone structural material means a material that can be used as a reticulated bone replacement material that can withstand the physiological compressive load experienced by the compressed backbone at least under normal physiological conditions. As such, the flowable paste-like materials of the present invention are described in Morgan, EF et al. (1997, Mechanical Properties of Carbonated Apatite Bone Mineral Sustitute: Strength, Fracture and Fatigue Behavior, J. Materials Science: Materials in Medicine, V. 8, 559-570), which is set into a product having a compressive strength of at least about 20, typically at least about 40, and more commonly at least about 50 MPa, wherein the compressive strength of the final apatite product is It can be as high as 60 MPa or more. Including silicates in the setting fluid lowers the liquid to solid ratio that must be used resulting in a significantly higher compressive strength. Compressive strength can be obtained in a range as high as 100 to 200 MPa. In certain embodiments, the resulting product is at least about 1 MPa, including at least about 5 MPa, at least about 10 MPa or more, such as from about 0.5 to about 10 MPa, as measured by tensile strength analysis shown in the experimental section below. And a tensile strength of at least about 0.5 MPa.

In representative embodiments, the resulting product is stable in vivo for an extended period of time, which does not dissolve or degrade (in bone) when implanted into living organisms under in vivo conditions, eg, for an extended period of time. Excludes the remodeling activity of the cells. In these embodiments, the resulting product may be stable for at least 4 months, at least 6 months, at least about 1 year or more, such as 2.5 years, 5 years, and the like. In certain embodiments, the resulting product is stable in vitro when placed in an aqueous environment for an extended period of time, which does not dissolve or degrade when immersed in an aqueous environment, for example, for an extended period of time. it means. In these embodiments, the resulting product may be stable for at least about 4 months, at least about 6 months, at least about 1 year or more, such as 2.5 years, 5 years, and the like.

In representative embodiments, the composition may be set in a fluid environment, for example in an in vivo environment at a bone reconstruction site. As such, the composition can be set in a wet environment, for example in an environment filled with blood and other physiological fluids. Thus, the site to which the composition is administered during use does not need to be kept dry.

Uses

The methods of the present invention and the compositions thus produced introduce a substance that can be set up into a solid calcium phosphate product into physiological sites of interest, such as for dental, craniofacial and orthopedic use, as described above. It is used in preferred applications. In orthopedic applications, cement will generally be prepared as described above and introduced into bone reconstruction sites, such as bone sites, including reticular and / or cortical bone. Orthopedic uses where the cements made with the systems of the present invention find particular use include the treatment of fracture and / or transplant augmentation in mammalian hosts, particularly in humans. In such fracture treatment methodologies, the fracture is first reduced. After fracture reduction, the flowable structural material produced by the system of the present invention is introduced into the reticular tissue in the fracture area using the delivery device. Certain dental, craniofacial and orthopedic signs in which the present invention is used include, but are not limited to, those disclosed in US Pat. No. 6,149,655, the disclosure of which is incorporated herein by reference. In addition to the specific uses disclosed in these US patents, the cement composition of the present invention is used in applications in which sternotomy is used. Specifically, the cements of the present invention are used in the suturing process of the sternum incision, where the bone fragments are joined again and wired together, and any remaining cracks are filled with the cement of the present invention. In yet other embodiments, the compositions of the present invention are used for drug delivery, where these compositions can act as drug depots that last for a long time after being administered to a physiological site. See US Pat. Nos. 5,904,718 and 5,968,253; Its disclosure is incorporated herein by reference.

In certain embodiments, vibration is used in connection with the minimum production of the target skeletal site. In the methods of the invention, the target skeletal site can be any of a variety of different skeletal sites. In many embodiments, the target skeletal region is an internal region of the bone as a reticulated region bounded by an internal target skeletal region, eg, cortical walls. Often, the target bone site is composed of reticular tissue, where it is desirable to penetrate orthopedic cement to create a reticular / cement composite structure. Representative reticular bone target sites of interest include, but are not limited to, those found in the following: vertebral bodies, Colles' fractures, adjacent humerus fractures, tibia plateau fractures, calcaneus fractures, and the like.

In these embodiments, vibration may be applied to the target bone site using any convenient protocol, depending on the desired result of using vibration to produce the target bone site. For example, in certain embodiments, preparation of the target bone site may include removing bone marrow, another substance from the bone site, for example, these methods may include a bone marrow or hematoma removal step, Wherein the substance, such as bone marrow, hematoma is removed before and / or during delivery of the cement composition at the target site to further enhance the penetration of the cement into the target site. For example, bone marrow can be removed from the target bone site by inspiration. More specifically, the bone marrow can be aspirated from one side of the target site as or before the cement is introduced into the other side. In these embodiments, vibrational power may be applied to the target bone site to enhance the rate and / or efficacy of removal of bone marrow, eg, lipid bone marrow.

In these particular representative embodiments, the vibrational force applied to the target bone site is in the range of about 1 Hz to about 100,000 Hz and about 5 microns, such as about 10 Hz to about 50,000 Hz, including about 100 Hz to about 1000 Hz. And from about 1 angstrom to about 5 mm, such as from about 1 micron to about 100 microns, including from about 50 microns. In certain representative embodiments, vibration is applied for a period of time ranging from about 0.1 seconds to about 10 minutes, such as from about 1 second to about 5 minutes, including from about 10 seconds to about 1 minute.

In certain embodiments, vibration is used in connection with the transfer of cement to the target site. In other words, vibrational power is applied to the cement composition while being delivered to the target site, such as the target bone site. In another way, the cement composition vibrates as it is delivered to the target bone site.

Although the cement composition may be vibrated using any convenient protocol, in many embodiments, the cement is vibrated by applying vibrational power to a cement delivery element, for example a needle carrying cement to a target bone site. For example, the amount of vibrational power applied to the cement through application to the transfer element is typically sufficient to provide a highly controlled penetration of the cement through the reticulated bone tissue. "Highly controlled infiltration" refers to the penetration of cement through the reticulated bone tissue in such a way that it can be stopped substantially simultaneously with the vibrating session, and when the vibration is stopped, the cement is no longer moved into the reticulated tissue, Any movement of cement into the network tissues continues for up to 5 seconds, for example about 1 to 3 seconds. When vibrational power is applied to cement by applying it to a transfer element for cement, the transfer element is in many embodiments from about 1 Hz to about 100,000 Hz, such as from about 10 Hz to about 10,000 vpm, including from about 100 Hz to about 1,000 Hz. And oscillating in a range, and having a force to move the transfer element at a bi-directional distance of about 1 micron to about 1 100 microns and about 1 angstroms to about 5.0 mm, including 5 microns to about 50 microns.

A feature of the methods of the present invention in certain of these embodiments is that the cement is delivered in such a way that it is provided with a highly controlled kinetic without the use of significant back-pressure for this cement. As such, any pressure applied to the cement during delivery does not exceed about 100 psi, and in certain embodiments is between about 1 to 100 psi. In certain these embodiments, negative pressure may be present at the target delivery site, where the negative pressure promotes the introduction of the cement composition into the target site. This negative pressure can be produced using any convenient protocol, such as the target site penetration protocol. If negative pressure is present at the target delivery site, this negative pressure may range from about 1 to about 1000 psi, including about 10 to about 100 psi.

Kits

Also provided are kits comprising the cements of the present invention, wherein the anhydrous liquid components may be present in separate containers within the kit, or some of the components may be in a container such as anhydrous ingredients in the first container, May be combined into one container, such as a kit present in a second container, wherein the containers may or may not be in a combined configuration as disclosed in US Pat. No. 6,149,655, the disclosure of which is incorporated herein by reference. Quote. In certain embodiments, the kits may include two or more fluids of different concentrations, for example, to provide a kit that is flexible with respect to the properties of the setting fluids prepared therefrom. For example, the kit may comprise two or more different phosphate-silicate solutions which are mutually differentiated with respect to their silicate and / or phosphate components. Alternatively, the kit may be comprised of many different discrete phosphate and / or silicate solutions that differ in terms of concentration and are mixed according to the use of the kit as desired to obtain the desired setting fluid. As noted above, the kit components may be in separate containers. Alternatively, these components may be provided in package elements such as those described above.

In addition to cement compositions, the kits of the present invention may further comprise many additional reagents, such as cells (as described above, where the compositions should be seeded), protein reagents (as described above), and the like. have.

The kits of the present invention comprise one or more additional components used in the manufacture and / or delivery of cement, such as mixing elements such as spatula, pestle and pestle; Delivery elements such as syringes; And the like may further be included.

In addition to the above components, kits of the invention typically further comprise instructions for using the components of the kit to practice the methods herein. Instructions for carrying out the methods are generally recorded on a suitable recording medium. For example, it may be printed on a substrate such as directive paper or plastic. As such, the directive may be present in the labeling of the container such as a kit or parts thereof as a package insert (ie, associated with packaging or subpackaging). In other embodiments, the directive is present as an electronic storage data file residing on a suitable computer readable storage medium, such as a CD-ROM. In still other embodiments, the actual directive is not present in the kit and means are provided for obtaining the directive from a remote source, for example via the Internet. An example of such an embodiment is a kit that includes a web address where the directive can be viewed and / or where the directive can be downloaded. As with these directives, this means of obtaining the directive is recorded on a suitable substrate.

The following examples are not intended to be limiting and provided for the purpose of illustration.

Experiment

I. Fast Setting Cement Formulations

A. Overview

Cement formulations consisting of a mixture of dicalcium phosphate anhydride and α-tricalcium phosphate mixed with dilute sodium silicate at pH = 11.0 using a liquid to powder ratio of 0.40 were investigated. Specific formulations tested were as follows:

B. Cement Formulations:

6.0g TCP 3082102

0.6 g DCPA

0.17 g MCPM  or SPMA

2.71 g NaSiO ₄ (2.5% by volume, 0.40 l / s, pH11.0)

6.0g TCP 3082102

0.6 g DCPA

0.19 g SPMM

2.71 g NaSiO ₄ (2.5% by volume, 0.40 l / s, pH11.0)

C. Results

The influence of different phosphate dihydrogen salts added and mixed in powder form within the same cement system was evaluated in terms of initial strength gain (setting) as measured by an improved Gilmore needle indentation test.

Salts tested include:

Name Source Molecular Formula Molecular Weight ( H ₂ PO ₄ Weight per mole

MCPM JT Baker Ca (H ₂ PO ₄ ) ₂ ㆍ H ₂ O 252.1 126.0

SPMA Sigma NaH ₂ PO ₄ 120.0 120.0

SPMM Sigma NaH ₂ PO ₄ ㆍ H ₂ O 138.0 138.0

Note: The moles of phosphate will be approximately equivalent to replacing MCPM with SPMA.

Monobasic sodium phosphate anhydride (SPMA) and monobasic sodium phosphate monohydrate (SPMM) salts were superior to monobasic calcium phosphate monohydrate (MCPM) as indicated by the following setting test results.

Setting value (Newtons)

MCPM SPMA SPMM

3 minutes 2.3 82.0 183

6 minutes 4.8 299.0 509

9 minutes 131.8 469.0 725

12 minutes 190.6 664.0 800

II. Fast Setting Cement Formulations with Carboxymethylcellulose

A. Overview

The effect of adding carboxymethylcellulose to commercially available Callos injection cement formulations (Skeletal Kinetics LLC, Cupertino, Calif.) Was observed.

B. Formulations

1. Injection formulation w / CMC:

1g 40-100 micron alpha TCP

1g 100-200 micron Alpha TCP

5g 3-4 micron alpha TCP

0.1g sodium phosphate

0.015g CMC

1: 100 dilute sodium silicate at 0.41 l / s

2. Impact Formulation w / CMC:

3g 100-200 micron Alpha TCP

8g 3-4 micron alpha TCP

0.125g Sodium Phosphate

0.03g CMC

1:50 dilute sodium silicate at 0.39 l / s

C. Results

1. Injection test (N = 6)

Injection testing was performed via a Merit Medallion 6cc syringe with a designated Mannin 11 gauge needle. The material is according to the Instructions for Use (IFU): the room temperature is adjusted to 19-21 ° C., the powder and liquid are mixed for 1 minute, the syringe is filled, the needle is attached and 3 minutes after mixing with the Instron machine. Infused and mixed. The results are provided in Table 1 below. In Table 1 below, "kit #" means the sample number of the powder-liquid set being used. "Starting volume (cc)" is the total amount of cement in the syringe measured from the bottom of the ruhr syringe to the volume indicated on that syringe. The "final fat (cc)" is the amount of cement remaining in the syringe after the injection process is complete. "Dynamic load (N)" is the median value of the load applied to the syringe plunger during material injection. This value indicates the relative viscosity of the cement and the ease of injection.

Table 1-Injection Test Kit # Starting volume (cc) Final buff (cc) Dynamic load (N) One 3.5 0.0 15 2 3.5 0.0 10 3 3.5 0.0 11 4 3.5 0.0 12 5 3.5 0.0 11 6 3.5 0.0 11 Average 3.5 0.0 12 Standard Deviation 0.0 0.0 2

2. Penetration test (N = 6)

Intrusion tests were performed through multiple syringe diameters to assess the infiltration capacity. The material is in accordance with the Instructions for Use (IFU): the room temperature is adjusted to 19-21 ° C., the powder and liquid are mixed for 1 minute, the syringe is filled, the needle is attached and 3 minutes after mixing the Instron machine By mixing and mixing. The results are provided in Table 2 below. In Table 2 below, “needle” means gauge size of needle diameter and needle length.

Table 2-Penetration Test Kit # needle Starting volume (cc) Final volume (cc) Dynamic load (N) One No needle 3.4 0.0 12 2 11g, 12cm 3.4 0.0 12 3 12g, 12cm 3.4 0.0 15 4 13g, 18cm 3.4 0.0 30 5 15 g, 13 cm 3.4 0.0 40 6 16 g, 2 cm 3.4 0.0 20 Average 3.4 0.0 Standard Deviation 0.0 0.0

3. Setting test (N = 6)

The setting test was performed as follows. The materials were mixed according to the IFU: ie, mixed for 1 minute, filled the setting molds correctly, immersed in a 32 ° C. bath 12 minutes after mixing and tested for setting values at designated times in the bath under an Instron machine. . The results are provided in Table 3 below. In Table 3, "3 minutes, 6 minutes, 12 minutes (N)" is the designated time that setting cubes need to be immersed before testing with an Instron machine.

Table 3-Setting Test Kit # 3 minutes (N) 6 minutes (N) 12 minutes (N) One 24.6 857.0 1064.0 2 9.0 778.1 1080.4 3 32.7 750.3 1052.7 4 54.2 885.6 994.9 5 33.0 873.5 819.1 6 13.2 697.5 1108.9 Average 27.8 802.0 1020.0 Standard Deviation 16.3 71.0 105.4

4. Tensile Strength Test (N = 4)

Tensile strength tests were performed as follows. The material was mixed according to IFU: ie, mixed for 1 minute, the setting molds were filled correctly, immersed in a 37 ° C. bath for 24 hours, and tested for tensile strength of diameter under an Instron machine. The results are provided in Table 4 below.

Table 4-Tensile Test Kit # 24 hours One 4.427 3.615 4.038 2 4.301 4.895 4.987 3 5.296 4.374 3.048 4 4.825 4.526 3.781 Average 4.343 Standard Deviation 0.641

5. Drill and screw test (N = 6)

Drilling and screw tests were performed as follows. The material is mixed according to the IFU: that is, mixing for 1 minute, filling the drilling cube molds correctly, immersing in a 32 ° C bath for 10 minutes, drilling a hole in the cement with a 1/8 "drill bit, matching the diameter The screw operation was performed with a self-drilling screw, which is shown in Table 5. The results are provided in Table 5. In Table 5, "drilling" and "screwing" are observational descriptions of the functional results during the test.

Table 5-Drill and Screw Tests Kit # Drilling Screwing One No crack / no problem No crack / no problem 2 No crack / no problem No crack / no problem 3 No crack / no problem No crack / no problem 4 No crack / no problem No crack / no problem 5 No crack / no problem No crack / no problem 6 No crack / no problem No crack / no problem Average Good! Good! Standard Deviation - -

6. Ease of Mixing

Ease of mixing was verified by mixing each of the above kits (kits used in test sections 1 to 5) while paying attention to quality and consistency during and after mixing according to the instructions. Mixing quality was evaluated by weighing the powder and liquid, measuring the pH level of the liquid, and calculating the liquid: solid ratio of the kits used for the setting and injection test.

The observed uniformity of the mixing was constant throughout the test. The kits were mixed in a slightly thicker creamy manner due to the larger viscosity formulation by CMC.

In Table 6 below, "powder (g)" was the weight in grams of powder component measured in one of the kits. “Liquid (g)” was the weight in grams of the liquid component measured in one of the kits. "pH" means pH level of the liquid component. "L: S ratio" is the calculated ratio of liquid / solid weight.

Table 6-Ease of Mixing / Consistency Kit # Powder (g) Liquid (g) pH L: S ratio One 4.86 1.99 11.0 0.409 2 4.86 2.00 10.93 0.412 3 4.87 1.99 10.94 0.409 4 4.86 1.99 10.94 0.409 5 4.86 1.99 10.96 0.409 6 4.86 1.99 10.96 0.409 7 4.88 1.98 10.87 0.406 8 4.87 1.99 10.91 0.409 9 4.86 1.99 10.90 0.409 10 4.88 1.96 10.92 0.402 11 4.85 2.00 10.92 0.412 12 4.86 1.97 10.92 0.405 Average 4.86 1.99 10.93 0.408 Standard Deviation 0.01 0.01 0.03 0.003

7. Notch Sensitivity Test for Fracture Roughness

Notch sensitivity testing was performed as follows. The materials were mixed according to IFU: that is, mixed for 1 minute, the notch sensitivity test molds were correctly filled and immersed in a 37 ° C bath for the designated time. Two kits were used to completely fill one notch sensitivity mold. To ensure maximum strength, the specimens were cured in a 37 ° C. bath for 4 days before testing. The results are provided in Table 7 below.

Table 7-Notch Sensitivity Test Kit # 96 hours One 88N

8. Summary

Table 8 Results for each of the test parameters reviewed above

Table 8 Test features Summary of results Injection Cement was injected 100% (final volume should be left 0.0cc) Intrusive Cement can be introduced through a modified injection device. setting The cement reached ≧ 450 N upon 6 min curing in a 32 ° C. warm PBS bath. The tensile strength The cement reached a tensile strength of ≧ 4.0 MPa after curing at 37 ° C. for 24 hours. Drill and screw The resulting cured sample was drilled and screwed after 10 minutes in a 32 ° C. PBS bath. Ease of mixing Cement was mixed with little effort within 1 minute.

D. Conclusion

The results provide complete injection of cement by adding carboxymethylcellulose to the injection formulation, while other functions of the cement remain similar to the original Callos ^™ injection product. In addition, with respect to impact formulations, the powders can mix well as compared to impact formulations lacking carboxymethylcellulose and have better handling properties.

From these results and discussions it is apparent that calcium phosphate cements set at high speed into the compositions at high strength are provided by the present invention. As such, the present invention significantly contributes to the art.

All publications and patent applications mentioned in this specification are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

While the present invention has been fully disclosed herein, it will be apparent to those skilled in the art that many changes and modifications may be made thereto without departing from the spirit and scope of the appended claims.

Claims (22)

(a) setting fluid; And (b) (i) calcium and phosphate sources; And     (ii) combining anhydrous reactants comprising monovalent cationic phosphate dihydrogen salt in a ratio sufficient to produce a calcium phosphate composition, wherein the calcium phosphate composition is set at high speed into the rigid calcium phosphate containing product. The method of claim 1, wherein the monovalent cation phosphate dihydrogen salt comprises at least one water by hydration. The monovalent cation phosphate dihydrogen salt of claim 1 wherein Y ⁺ H ₂ PO ₄ ㆍ (H ₂ O) _n (here, Y ⁺ is a monovalent cation such as K + or Na +; n is an integer from 0 to 2). The method of claim 3, wherein Y ⁺ is Na +. The method of claim 5, wherein the monovalent cation sodium dihydrogen phosphate salt is NaH ₂ PO ₄ or NaH ₂ PO ₄ .H ₂ O. The method of claim 1, wherein the monovalent cation phosphate dihydrogen salt is present in the composition in an amount ranging from about 0.10 to about 10 weight percent. The method of claim 1, further comprising combining an emulsifier with the setting fluid and anhydrous reactants to produce the calcium phosphate composition. 8. The method of claim 7, wherein the emulsifier is cellulose ether. The method of claim 8, wherein the cellulose ether is carboxymethylcellulose. The method of claim 1, wherein the setting fluid is a solution of soluble silicate. The method of claim 1, wherein the composition achieves an intensity of at least about 50 Newtons within 3 minutes. The method of claim 1, wherein the composition achieves an intensity of at least about 250 Newtons in 6 minutes. A composition which is set into a calcium phosphate containing product and produced by the method according to claim 1. The composition of claim 13, wherein the composition obtains an intensity of at least about 50 Newtons within three minutes. A method of reconstructing a hard tissue defect, the method comprising: applying to a hard tissue defect site a composition, which is set into a calcium phosphate containing product and produced by the method according to claim 1. (a) (i) calcium and phosphate sources; And     (ii) anhydrous reactants including monovalent cation phosphate dihydrogen salts; And (b) a kit for use in preparing a composition comprising a setting fluid or components that produce the same, wherein the composition is set into a calcium phosphate product in an in vivo fluid environment. The kit of claim 16, wherein the setting fluid is a solution of soluble silicate. The kit of claim 16 further comprising an emulsifier. 19. The kit of claim 18, wherein said emulsifier is cellulose ether. 20. The kit of claim 19, wherein said cellulose ether is carboxymethylcellulose. The kit of claim 16 further comprising a mixing element for preparing a settable composition from the anhydrous reactants and the setting fluid. The kit of claim 16 further comprising a delivery element.